Antiandrogen bicalutamide promotes tumor growth in a novel androgen-dependent prostate cancer xenograft model derived from a bicalutamide-treated patient
Antiandrogen bicalutamide promotes tumor growth in a novel androgen-dependent prostate cancer xenograft model derived from a bicalutamide-treated patient
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DOI：
10.1158/0008-5472.can-05-0817
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发表时间：
2005-11-01
期刊：
影响因子：
11.2
通讯作者：
Ogawa, O
中科院分区：
文献类型：
--
作者：
Yoshida, T;Kinoshita, H;Ogawa, O
雄激素消融治疗在控制前列腺癌方面是有效的。尽管大多数癌症在雄激素消入术后仍会复发和进展，但一些患者会出现抗雄激素戒断综合征，即停用抗雄激素治疗的患者表现出临床改善。尽管雄激素受体（AR）被认为在雄激素消融后的前列腺癌进展中发挥重要作用，但有限的组织分子研究和少量的人类前列腺癌细胞系限制了前列腺癌的研究。在这里，我们描述了KUCaP，一种新的连续移植的人类前列腺癌异种移植模型。我们从一位接受抗雄激素比卡鲁胺治疗的患者的肝转移组织中建立了KUCaP。KUCaP在配体结合域的741个氨基酸（色氨酸到半胱氨酸；W741C）点突变表达AR。这种突变也存在于用于产生KUCaP的癌组织中。虽然KUCaP在雄性小鼠体内的生长是雄激素依赖性的，但比卡鲁胺异常促进了KUCaP的生长和前列腺特异性抗原的产生。我们首次展示了比卡鲁胺对临床诱导AR突变的异种移植物的激动作用。这种比卡鲁胺应答突变AR将有助于开发雄激素消融抵抗性前列腺癌的新疗法。
Androgen ablation therapies are effective in controlling prostate cancer. Although most cancers relapse and progress despite androgen ablation, some patients experience antiandrogen withdrawal syndrome, in which those treated with antiandrogen show clinical improvement when antiandrogen is discontinued. Although the androgen receptor (AR) is suggested to play an important role in prostate cancer progression even after the androgen ablation, limited tissue availability for molecular studies and small numbers of human prostate cancer cell lines have restricted prostate cancer research. Here, we describe KUCaP, a novel serially transplantable human prostate cancer xenograft model. We established KUCaP from liver metastatic tissue of a patient treated with antiandrogen bicalutamide. KUCaP expressed the AR with a point mutation at amino acid 741 (tryptophan to cysteine; W741C) in the ligand-binding domain. This mutation was also present in cancerous tissue used for generation of KUCaP. Although the growth of KUCaP in male mice was androgen dependent, bicalutamide aberrantly promoted the growth and prostate-specific antigen production of KUCaP. For the first time, we show the agonistic effect of bicalutamide to a xenograft with clinically induced AR mutation. This bicalutamide-responsive mutant AR will serve in the development of new therapies for androgen ablation-resistant prostate cancers.